The proposed research concerns the development of methods for the chemical synthesis of stereochemically complex medium- and large-ring carbocyclic compounds, and the application of these methods to the total synthesis of anti-neoplastic and biologically important macrocyclic natural products. In spite of the importance of these compounds, little progress has been made toward their synthesis because few general synthetic methods exist for the construction of complex, flexible carbon chains of defined stereochemistry. Several methods for the stereoselective elaboration of conformationally flexible carbon chains will be studied, including stereocontrolled oxidative addition to alkenes, cyclopropyloxirane fragmentation, and Claisen rearrangement of lactate esters. These methods will then be applied toward syntheses of nonactic acid, the rifamycins and streptovaricins, the antileukemic Maytenus macrocycles, the macrolide antibiotics, and the necic acids derived from the pyrrolizidine alkaloids, as appropriate. In addition, a procedure for the synthesis of large-ring lactams via the Claisen rearrangement of N-allyl amides will also be investigated.